Functional Medicine University s Functional Diagnostic Medicine Training Program

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1 Functional Diagnostic Medicine Training Program MOD 4 * FDMT533A The Physiology of Insulin Resistance (Oxidative Stress and Diabetes) Limits of Liability & Disclaimer of Warranty We have designed this book to provide information in regard to the subject matter covered. It is made available with the understanding that the authors are not liable for the misconceptions or misuse of information provided. The purpose of this book is to educate. It is not meant to be a comprehensive source for the topic covered, and is not intended as a substitute for medical diagnosis or treatment, or intended as a substitute for medical counseling. Information contained in this book should not be construed as a claim or representation that any treatment, process or interpretation mentioned constitutes a cure, palliative, or ameliorative. The information covered is intended to supplement the practitioner s knowledge of their patient. It should be considered as adjunctive and support to other diagnostic medical procedures. This material contains elements protected under International and Federal Copyright laws and treaties. Any unauthorized reprint or use of this material is prohibited. Functional Medicine University; /Insider s Guide Module 4: FDMT 533A: Physiology of Insulin Resistance (Oxidative Stress and Diabetes) Copyright 2010 Functional Medicine University, All Rights Reserved

2 Contents Anatomy and Physiology of the Pancreas 2 Insulin Structure and Synthesis and Secretion 3 The Insulin Receptor 5 The Physiological Effects of Insulin 5 Insulin Resistance 7 Laboratory Assessment of Serum Insulin 9 Oxidative Stress and Diabetes 10 References 13 1

3 Anatomy and Physiology of the Pancreas The pancreas has both endocrine and exocrine functions. The exocrine function is involved with the digestive process, while the endocrine function secretes several hormones that regulate glucose, lipid and protein metabolism. The tissues of the pancreas consist of the acini, which secrete digestive juices; and the islets of Langerhans, which mainly secrete insulin and glucagon. The islets of Langerhans are innervated by the sympathetic and parasympathetic nervous system. The islets of Langerhans house three major cell types: Alpha cells secrete glucagon Beta cells secrete insulin and amylin (60% of all the cells in the islets of Langerhans are the beta cells. Amylin inhibits the secretion of insulin) Delta cells secrete somatostatin (Somatostatin is also known as growth hormone inhibitory hormone. Somatostatin is also secreted by the hypothalamus and the gastrointestinal system. Somatostatin inhibits the secretion of insulin and glucagon.) 2

4 Insulin Structure and Synthesis and Secretion Insulin is synthesized in the beta cells. Its structure is composed of two chains of amino acids held together by disulfide bonds. Insulin is secreted from the beta cells when appropriately stimulated, primarily in response to elevated blood glucose concentration. The cells import glucose by a process called facilitative diffusion mediated by membrane transport proteins. In the cell membrane of the beta cells are a large number of these membrane transport proteins called glucose transporters (GLUT-2). The GLUT-2 transports glucose in the beta cells in proportion to the blood glucose concentration. 3

5 As glucose enters the cell, it is phosphorylated into glucose-6-phosphate. Glucose-6-phosphate is then oxidized to ATP ATP closes potassium channels, which depolarizes the cell membrane Depolarization of the cell membrane open calcium channels, allowing the influx of calcium Influx of calcium in the cell stimulates the release of insulin from the beta cells Note: A class of drugs called sulfonylurea is used in the treatment of type II diabetes. It works by blocking the potassium channels. Other Factors That Stimulate Insulin Secretion Amino acids (In particular, arginine and lysine) Amino acids administered by themselves cause a small secretion of insulin, however when combined with glucose, insulin secretion may be doubled, especially in the presence of excess protein. Gastrointestinal hormones gastrin, cholecystokinin, and gastric inhibitory peptide. Other hormones that directly increase insulin secretion or potentiate the glucose stimulus for insulin secretion growth hormone, cortisol, glucagon NOTE: PROLONGED SECRETION OF ANY HORMONES THAT STIMULATES INSULIN SECRETION CAN LEAD TO DIABETES BY EXHAUSTING THE BETA CELLS. Insulin is usually cleared from blood circulation within 10 to 15 minutes. It is interesting to note that insulin is biologically active from one mammal to another. Insulin is considered an anabolic hormone. Aside from the fact that insulin s primary function is to regulate cellular uptake of glucose, it also functions to increase growth, synthesis DNA and cause cell replication. Insulin may also affect neural tissue and modulate neural metabolism, synapse activity and feeding behaviors. 4

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7 The Insulin Receptor Functional Medicine University s Insulin receptors are integrated in the cell plasma membrane. The receptors are composed of four subunits (two alpha and two beta) held together by disulfide bonds. Insulin binds to the alpha subunits, which are extracellular. This binding causes the beta subunits to phosphorylate themselves. This process is called autophosphorylation. The autophosphorylation of the beta subunits then activates a protein called tyrosine kinase. Tyrosine kinase modulates a wide variety of cellular events, including differentiation, growth, metabolism and apoptosis. In the case of the insulin receptor, tyrosine kinase causes the phosphorylation of a group of enzymes called insulin-receptor substrates (IRS). IRS initiates glucose transport in the cell, protein synthesis, fat synthesis, glucose synthesis, and growth and gene expression. As you can read from this description, insulin not only affects carbohydrate metabolism, it also affects fat and protein metabolism just as equally. This is exemplified in the fact that patients with prolonged diabetes have a diminished ability to synthesize proteins which leads to tissue wasting. The Physiological Effects of Insulin Insulin is secreted directly into the portal vein, and subsequently to the liver, where it exerts profound metabolic effects. As stated earlier, these effects are the response of the activation of the insulin receptors. Effects of Insulin on Carbohydrate Metabolism Insulin promote muscle glucose uptake and metabolism Insulin promotes liver uptake, storage, and use of glucose Insulin promotes conversion of excess glucose into fatty acids and inhibits gluconeogenesis in the liver (When the liver s glycogen capacity if full, insulin promotes the conversion of excess glucose into fatty acids. The fatty acids combine with glycerol to from triglycerides and are transported to the adipose tissue as VLDL very low density lipoproteins- and subsequently deposited as fat.) Note: Exercise makes the muscle fibers more permeable to glucose even in the absence of insulin. This is due to the fact that muscle contraction by itself causes an increase in permeability. Effects of Insulin of Fat Metabolism Insulin promotes fat synthesis and storage (Increased fatty acid synthesis attributed to insulin increasing the transport of glucose to the liver, which converts glucose to fatty acid, which is then formed into triglycerides and stored.) Insulin deficiency increases use of fat for energy. Insulin deficiency causes lipolysis of storage fat and release of free fatty acids. The increased fatty acids in the plasma promote the liver to convert some of the fatty acids into cholesterol, triglycerides and phospholipids. Cholesterol, phospholipids and triglycerides are then transported into the blood stream as lipoproteins. Insulin deficiency leads to ketosis and acidosis Since the body use of glucose for energy is decrease, fat becomes the primary source of energy. Fat is utilized for energy through the process of beta-oxidation. Excess beta-oxidation causes increased amounts of acetyl-coa, which is then condensed to form acetoacetic acid. Some of the acetoacetic will be converted into beta-hydroxybutyric acid (3-hydroxybutyric acid) and acetone, all of which are ketone bodies leading to ketosis. 6

8 Effects of Insulin on Protein Metabolism Insulin promotes protein synthesis and storage (Insulin stimulates the transport of amino acids into the cell. Most notably are the branched-chain amino acid, leucine, isoleucine and valine, as well as, tyrosine and phenylalanine. Insulin increases the translation of mrna causing protein synthesis) Insulin deficiency causes protein depletion and increased plasma amino acids (protein wasting) Insulin and growth hormone interact synergistically to promote growth Summary of Effects of Insulin on Target Tissue Cells Increased cellular uptake of glucose Increased protein synthesis Increased glycogen synthesis Increased amino acid uptake Increased potassium uptake Decreased protein degradation Decreased lipolysis Decreased gluconeogenesis Factors That Increase Insulin Secretion Increased blood glucose, free fatty acids and amino acids Gastrointestinal hormones (gastrin, cholecystokinin, secretin, gastric inhibitory peptide) Gastric inhibitory peptide (GIP) is a member of the secretin family. GIP inhibits gastric motility and secretion of acid. Cortisol, glucagon, and growth hormone (Glucagon is secreted from the alpha cells of the islets of Langerhans when the blood glucose concentration falls. Glucagon works in direct opposition to insulin in most cases. The major effects of glucagon are glycogenolysis and gluconeogenesis. Both of these actions occur in the liver). Insulin resistance Diabetic medications Parasympathetic stimulation Beta-adrenergic stimulation ( recall that the main stimulator of beta-adrenergic receptors is adrenalin) Factors that Decrease Insulin Secretion Decreased blood glucose Somatostatin (Somatostatin inhibits the secretion of many hormones including insulin and glucagon. Somatostatin in secreted by the pancreas, gastrointestinal tract, hypothalamus and other regions of the central nervous system. Alpha-adrenergic activity Leptin (Leptin is a protein hormone expressed mainly by the adipocytes, and to a lesser extent by the epithelium of the stomach and the placenta. Leptin receptors are mainly located in the hypothalamus. The physiological effects of leptin include regulation of food intake, energy expenditure and body weight. ) 7

9 Insulin Resistance Functional Medicine University s Insulin resistance is a condition in which the body produces insulin but does not use it properly. When insulin-sensitive tissues (muscle, fat and liver) fail to respond and lower circulating glucose, the pancreas attempts to secrete greater levels of insulin. The resulting hyperinsulinemia in a patient with normal blood glucose concentration is referred to as insulin resistance. Eventually, the pancreas fails to keep up with the body s need for insulin, causing excess glucose to build up in the bloodstream, and thus setting the stage for diabetes. Insulin resistance and impaired glucose metabolism is generally a gradual process that is associated with weight gain and obesity. The mechanisms linked to insulin resistance include genetic defects, autoantibodies to insulin and insulin receptors, and accelerated insulin degradation. Obesity is the most common cause of insulin resistance, and is associated with a decrease in the number of insulin receptors and failure of the receptors to active tyrosine kinase. Omentin is a protein expressed and secreted from visceral adipose tissue but not in subcutaneous adipose tissue. Omentin increases insulin sensitivity in adipocytes. The genetic expression of both plasma omentin 1 and plasma omentin 2 were decreased with obesity and were correlated with visceral adipose tissue. Syndromes of insulin resistance include: Obesity Glucose intolerance Metabolic syndrome (syndrome X/Dysmetabolic syndrome) Diabetes Metabolic Syndrome Insulin resistance plays a major pathogenic role in the development of metabolic syndrome. Metabolic syndrome is defined as the presence of any of the three following conditions: Waist measurement of 40 inches or more for men and 35 inches or more for women Triglyceride levels of 150 mg/dl or above, or taking medication for elevated triglycerides HDL level below 40mg/dL for men and below 50 mg/dl for women or taking medications for low HDL level Blood pressure of 130/85 or above, or taking medication for elevated blood pressure Fasting blood glucose levels 100 mg/dl or above or taking medication for elevated blood glucose levels Recent studies suggest that insulin resistance appears to be caused by abnormalities in the signaling pathways that link receptor activation with multiple cellular effects. A recent article in the Annual Review of Physiology (Vol. 72: March 2010) stated that insulin resistance in the setting of obesity results from a combination of altered functions of insulin target cells and the accumulation of macrophages that secrete pro-inflammatory mediators. The study showed that at the molecular level, insulin resistance is promoted by increased macrophage activity, in other words, the inflammatory process. Increased levels of acute-phase reactants, especially CRP have been associated with insulin resistance and metabolic syndrome. Another article in Physiology (Vol. 19, No.4, , August 2004) titled Unraveling the Cellular Mechanism of Insulin Resistance in Humans: New Insights from Magnetic Resonance Spectroscopy, revealed the following: defects in mitochondrial function, be it acquired or inherited, may lead to insulin resistance; the potential role of the inflammatory pathway in insulin resistance: increased plasma fatty acids cause insulin resistance by interfering with insulin-stimulated glucose transport activity; and that any perturbation that leads to an increase in intramyocellular 8

10 fatty acid metabolite (e.g. fatty acyl-coa and diacylglycerol)content, such as acquired or inherited defects in fatty acid oxidation, defects in adipocyte fat metabolism (e.g. lipodystrophy lipid accumulation in the liver- acquired or genetic) leading to increased fat delivery to liver and muscle, or, most commonly, increased fat delivery due to increased caloric intake, will lead to insulin resistance. The Possible Clinical Presentations of Insulin Resistance Obesity Hypoglycemia Metabolic syndrome Hypertension Dyslipidemia Polycystic ovary syndrome Cardiovascular disease 9

11 Laboratory Assessment of Serum Insulin The normal fasting adult serum insulin levels is 6-26 microunit/ml (or pmol/L SI units). Normal weight women were found to have a mean fasting level insulin level of 10 microunit/ml. Obese women had a fasting level of 15 microunit/ml and those with insulin resistance had levels ranging from 20 to 25 microunit/ml. Within one hour of an oral glucose load, insulin levels increased up to 50mU/mL in normal weight women, up to 60 in obese women and from 120 to 180 in those with insulin resistance. Higher levels of circulating insulin affects energy metabolism by increasing synthesis of triglycerides and cholesterol, leading to increased serum levels of triglycerides and LDL cholesterol. From a functional medicine perspective, fasting serum insulin concentrations above 10mU/mL indicate possible insulinemia associated with insulin resistance. Increased level of serum insulin can also be caused by; Cushing syndrome, acromegaly, and an insulinoma, which is a tumor on the beta cells of the islets of Langerhans (patients will have hyperinsulinemia and hypoglycemia). Decreased serum insulin levels are seen in insulin-dependent diabetes and hypopituitarism. In Summary In summary, insulin resistance begins with hyperinsulinemia with glucose control. During that time there is an increased cellular resistance to insulin, overproduction of free fatty acids by the adipocytes and inability to suppress hepatic glucose production. This leads to metabolic syndrome causing increased blood glucose levels with hyperinsulinemia. Eventually, the patient is diagnosed with diabetes due to a decrease in insulin production. Also keep in mind that there are numerous diseases associated with insulin resistance. These include; cardiovascular disease, hypertension, polycystic ovary syndrome, cancer and nonalcoholic fatty liver disease. Hyperinsulinemia causes increased renal sodium retention and increased potassium excretion, as well as, increased activity in the sympathetic nervous system leading to hypertension. In PCOS, there is an excess secretion of luteinizing hormone. Insulin resistance and hyperinsulinemia stimulates ovarian production of androgen as well as reducing serum levels of sex hormone binding globulin. The net effect of this is increased testosterone levels, which can lead to PCOS, irregular menstruation and hirsutism. Oxidative Stress and Diabetes Chronic increased blood glucose concentration is known to cause toxic effects on the structure and function of organs systems, including the pancreas. The term glucose toxicity has been given to the deterioration of the beta cells of the islets of Langerhans due to chronic hyperglycemia. The mechanism through which chronically elevated blood glucose initiate damage to the beta cells is by increased production of reactive oxygen species and accelerated apoptosis. The consequence of oxidative stress (increased ROS) on beta cell function is to cause abnormal insulin gene expression, decrease insulin content and decrease insulin secretion. 10

12 There are six biochemical pathways which glucose metabolism can form reactive oxygen species. Under normal physiologic conditions, glucose is primarily metabolized by glycolysis, with the metabolic end products proceeding to the Krebs cycle and oxidative phosphorylation 6. Under pathologic conditions of hyperglycemia, excessive glucose levels can overwhelm the glycolysis process and inhibit glyceraldehyde catabolism, which cause glucose shunting to other pathways: all of which produce reactive oxygen species. 11

13 In Summary In summary, reduction of oxidative stress and assessment of antioxidant status is primary in the treatment of insulin resistance and in both type 1 and type 2 diabetes. The utilization of primary and advanced functional medicine testing is paramount in evaluating all patients with insulin resistance and diabetes. Evidence of the efficacy of antioxidant therapy is accumulating, and should be assessed on all patients with glucose dysregulation. 12

14 References 1. Mosby s Manual of Diagnostic and Laboratory Tests, 2006, Mosby, Inc. 2. Reducing Oxidative Stress in Patients with Type 2 Diabetes Mellitus: A Primary Care Call to Action, Jeff Unger, MD; Pub., Catalina Research Institute, Chino, CA; 2008 Excerpta Medica, Inc. 3. Textbook of Medical Physiology, 11 th ed., Arthur C. Guyton, M.D. ϯ, John E. Hall, Ph.D. 4. Insulin-History, Biochemistry, Physiology and Pharmacology, Shashank R. Joshi, Rakesh M. Parikh, A.D. Das; Supplement of JAPI, July 2007, Vol. 55; 5. Omentin Plasma Levels and Gene Expression Are Decreased in Obesity, Batista, Yang, Lee, Glynn. Yu, Pray, Ndubuizu, Patil, Swartz, Kligman, Fried, Gong, Suldiner, Pollin, McLenithan; Article, DIABETES, Vol.56, June Chronic Oxidative Stress as a Central Mechanism for Glucose Toxicity in Pancreatic Islet Beta Cells in Diabetes, R. Paul Robertson; The Journal of Biological Chemistry, Vol. 279, No.41 October 8, 2004, pp Unraveling the Cellular Mechanism of Insulin Resistance in Humans: New Insights from Magnetic Resonance Spectroscopy; Physiology, Vol. 19, No.4, pp , August Insulin Resistance and Pre-diabetes, National Diabetes Information Clearinghouse; National Institutes of Health 9. Macrophages, Inflammation, and Insulin Resistance, Olefsky and Glass; Abstract, Laboratory Evaluations for Integrative and Functional Medicine, 2 nd ed., Richard S. Lord, and J. Alexander Bralley 13